Cancer is the leading cause of death in the world population. In 2008, there were an estimated 12.7 million new cancer cases diagnosed and 7.6 million deaths from cancer around the world according to <<Global Cancer Facts & Figures 2nd Edition>>. American Cancer Society estimates in 2012 over 1.6 million new cancer cases and about 577,000 deaths resulted from cancer in the United States in “Cancer Facts & Figures 2012”. By 2030, the global burden is expected to grow to 21.4 million new cancer cases and 13.2 million cancer deaths. Although there are a few promising options for cancer prevention, treatment mainly involves surgical removal of tumor or cancer and surrounding tissue plus chemotherapy and radiotherapy or chemotherapy alone or in combination with radiation without surgery. Various new drugs were developed for specific cancer in chemotherapy. Most often, chemotherapy is limited by severe side effects and dose limiting toxicity. Not only these chemotherapy caused side effects worsen patients' quality of life, but it can also result in stopping potentially curative treatment. So far, it still is a great challenge to find effective treatment with no/low adverse effects.
Increasing number of cancer patients uses plants, vegetables, herbs, and spices or its derived products as traditional medicine or alternative medicine. At least half of cancer patients in the United States use complementary and alternative medicine, exclusively or concurrently with traditional therapeutic regime such as radiation therapy and/or chemotherapy. It is ideal to develop drug or treatment from in fruits, vegetables, herbs and spices that are efficacious and without adverse side effect. Most preferably, a product or products can be invented to prevent development of various cancers and other diseases. This invention relates to improvements in human nutrition and therapeutics involving providing unique compositions with enriched or purified natural crocin and crocetin and/or other phytochemicals constituting anti-cancer compositions which can prevent, reduce and treat cancer as well as prevent or treat other diseases and conditions, including age-related and neurodegenerative disorders such as Alzheimer's and Parkinson's diseases, cardiovascular and cerebrovascular disease, digestive system diseases, toxin and alcohol caused liver injuries. The compositions can be used alone against cancer and protect normal cells and organs, or used in combination with other chemotherapy in a synergistic fashion that serve as sensitizer to more effectively kill abnormal cells while protect normal cells and organs at lower chemo dose, or in combination with radiotherapy against cancers and protect normal cells and organs undergoing radiation.
Crocin and crocetin exist in Crocus. They are the chemical components with antioxidative properties primarily responsible for the color of the stigmas of Crocus sativus L. (Saffron). Crocetin is a carotenoid dicarboxylic acid with 20 carbon atoms and it is the core of crocin. Crocin, in general term, includes Crocin-I (Crocetin-di-beta -D-gentiobiosyl ester), Crocin-II (Crocetin-beta-D-gentiobiosyl-beta-D-glucosyl ester), Crocin-III (Crocetin-mono-beta-D-gentiobiosyl ester), Crocin-IV (beta-D-monoglucoside ester of monomethyl alpha-crocetin), Crocetin-di-(beta-D-glucosyl) ester, Crocetin-mono-beta -D-glucosyl ester. Crocin mainly exists in trans-form, but can also present in cis-form in minor amount.
To demonstrate a few, chemical structure of crocetin (alpha-crocetin) is shown below:
Chemical structure of Crocin-I (Crocetin-di-beta-D-gentiobiosyl ester) is shown below:
Chemical structure of Crocin-II (Crocetin-beta-D-gentiobiosyl-beta-D-glucosyl ester) is provided below:
Chemical structure of Crocin-III (Crocetin-mono-beta-D-gentiobiosyl ester) is shown below:

Saffron is used as coloring and flavoring agents in the preparation of food in different parts of the world and has been used since ancient times for strengthening digestion, relieving coughs, smoothing menstruation, relaxing muscle spasms, improving mood, calming anxiety, preventing depression and enhancing men's sexual ability. Saffron is also used as health tonic. It is believed that regular intake of saffron with milk helps to build resistance against common cold and asthma. In recent years, Saffron is reported to possess anti-oxidant and anti-cancer effects among a wide range of pharmacological activities (Abdullaev F I. 2002, Chermahini S H. 2010, and Bhargavak V. 2011).
Commercial saffron is produced in Azerbaijan, France, Greece, India, Iran, Italy, Spain, China, Israel, Morocco, Turkey, Egypt, and Mexico from dried stigmas of cultivated Crocus sativus L. Each flower has only three small stigmas. It takes about 75,000 flowers to produce one pound of saffron. Currently, Saffron is produced worldwide at an annual rate of about 300 tons and harvested by hand, making Saffron an extremely expensive commodity with very limited supply. Saffron is safe to use. Saffron and saffron extracts have been safely used as spice, food coloring or for medicinal purposes for hundreds of years. Saffron is regarded as a food by Joint FAO/WHO Expert Committee on Food Additives (TRS 733-JECFA 29/33) and listed as substance Generally Recognized As Safe (GRAS) by FDA [CITE: 21CFR182.10, Revised as of Apr. 1, 2012].
Another source of crocin and crocetin is the gardenia fruit, Gardenia jasminoides Ellis or Gardenia augusta Merrill var. grandiflora Hort. Content of crocin in gardenia fruits increases when ripening. Gardenia fruits have been used in China and Japan as traditional medicine for its antiphlogistic, diuretic, and cholagogic effects. Gardenia fruit is listed and approved in 1998 by Chinese government both as food and as medicine and listed in The Japanese Pharmacopoeia as crude drug and in the list of existing food additives (Yoshiaki Kato 2000). Its extract, gardenia yellow, has also been listed as INS. 164 by JECFA (1989) as a food additive for colorant and widely used to give yellow color to food products such as noodle, pasta, candy, beverage and pickled products in Japan. Gardenia yellow has almost the same crocin and crocetin derivatives as saffron, only different in composition ratio of crocin and crocetin derivatives (Carmona M. 2006, Chen Y. & Zhang H.2008).
Studies have shown saffron extracts have anti-cancer activities. The anticancer/antitumor properties of crude extracts of saffron have been demonstrated in vitro and in vivo (Nair S C 1991, 1994, Abdullaev F I. 2002, 2003, Chryssanthi D G. 2007, Bakshi H. 2010). Crocin in saffron causes apoptosis in different type cancer cells. It is of great interest that non-tumor cells in culture appear to be insensitive to the effects of such extracts compared with tumor cells. Even saffron extract was found to stimulate or support in vivo growth of normal human lung cells (Abdullaev F I, 1992a,b).
Saffron aqueous extract rich in crocin was found protect animal against genetic damage induced by anti-cancer agents (Premkumar K. 2006). In this study, to ascertain the chemoprotective potential of saffron against the genotoxicity of three well-known anti-tumor drugs-cisplatin (CIS), cyclophosphamide (CPH) and mitomycin C (MMC)-using comet assay, Three doses of saffron (20, 40 and 80 mg/kg b.w.) were orally administered to mice for five consecutive days prior to the administration of anti-tumor drugs under investigation. Pre-treatment with saffron significantly inhibited anti-tumor drugs induced cellular DNA damage (strand breaks) as revealed by decreased comet tail length, tail moment and percent DNA in the tail.
Formation of toxic amyloid structures is believed to be associated with various late-onset neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. One human study (Akhondzadeh 2010) was carried out to investigate saffron may inhibit the aggregation and deposition of amyloid 0 in the human brain and may therefore be useful in Alzheimer's disease (AD). Fifty four patients were screened for a 22-week, double-blind study of parallel groups of patients with mild to moderate AD. The psychometric measures, which included AD assessment scale-cognitive subscale (ADAS-cog), and clinical dementia rating scale-sums of boxes, were performed to monitor the global cognitive and clinical profiles of the patients. Patients were randomly assigned to receive capsule saffron 30 mg/day (15 mg twice per day) (Group A) or donepezil 10 mg/day (5 mg twice per day) for a 22-week study. Saffron at this dose was found to be effective similar to donepezil in the treatment of mild-to-moderate AD after 22 weeks, while the donepezil group experienced significant frequency of vomiting.
Alcohols or ethanol over consumption is known to impair learning and memory. The acute effects of an alcohol extract of Crocus sativus L (saffron) were studied on learning and memory in step through and step down tests in normal as well as in learning- and memory-impaired mice (Zhang 1994). Saffron extract reduced the ethanol-induced impairment of memory registration both in step through and step down tests and the ethanol-induced impairment of memory retrieval in step down test. Saffron extract decreased the motor activity and prolonged the sleeping time induced by hexobarbital. It was suggested that saffron extract ameliorates the impairment effects of ethanol on learning and memory processes, and possesses a sedative effect. In behavioral and electrophysiological studies (Abe K. 2000), Saffron extract improved ethanol-induced impairments of learning behaviors in mice, and prevented ethanol-induced inhibition of hippocampal long-term potentiation, a form of activity-dependent synaptic plasticity that may underly learning and memory. This beneficial effect of saffron extract is attributed to crocin (crocetin di-gentiobiose ester), but not crocetin. It was indicated that Saffron extract or its active constituents, crocetin and crocin, could be useful as a treatment for neurodegenerative disorders accompanying memory impairment.
Dietary saffron was found in animal study (Maccarone R. 2008) maintains morphology and function after exposure to damaging light in mammalian retina. The photoreceptor layer was largely preserved in saffron-treated animals. Rate of photoreceptor death induced by the damaging bright continuous light drastically reduced in saffron treated animals. Saffron supplement was found to improve retinal flicker sensitivity in early age-related macular degeneration (AMD) (Falsini B. 2010). Followed up clinical study in Italy and Australia supported saffron supplementation and indicated crocin and crocetin as key actives to provide sustained benefits to central retinal function for AMD patients (Piccardi M. 2012)
Though saffron is reported to possess anti-oxidant and anti-cancer effects among a wide range of pharmacological activities, it is these main components, crocin and crocetin that were indicated to provide these pharmacological activities. Due to the very limited source and expensiveness of saffron, it is unrealistic to produce large scale of highly enriched crocin and crocetin from saffron. Saffron quality and its content of crocin and crocetin vary significantly, range from less than 1% to 20% (Alonso G L. 2001, Lechtenberg M. 2008). Quantification study of saffron also indicated a high amount of adulterant on the saffron market (Lechtenberg M. 2008). Chemically synthesized crocetin and its salts are not natural and not identical to natural crocin and crocetin, and may possess very different biologically and pharmacologically properties. Gardenia fruits, gardenia extracts, or gardenia yellow provide a feasible source to enrich and purify industrial scale of natural and high purity crocin and/or crocetin for wide applications. Enrich and purified crocin and/or crocetin render means to quantitatively and consistently deliver the actives in formulated products for preventing and treating cancers and other diseases.
Many other phytochemicals (organic chemicals from plant source) also have extensive and variety of health benefits in preventing or treating diseases or cancers. A few examples are provided here. Resveratrol in grape has been studied and reported to have anti-cancer effects, anti-inflammatory effects, cardiovascular benefits, anti-diabetes potential, energy endurance enhancement, and protection against Alzheimer's (Baur J A 2006). Curcuminoids, include curcumin, demethoxycurcumin, and bisdemethoxycurcumin, are polyphenolic pigments found in the spice turmeric. Curcumin has been widely studied and indicated to have anticancer, anti-inflammatory, antiviral, hypocholestrolemic and break-up of beta-amyloid plaques in brain activities (Aggarwal B B. 2007). Tea polyphenols, including catechin, epicatechin, epicatechin gallate, epigallocatechin, epigallocatechin gallate, theaflavin, theaflavin-3,3′-digallate, theaflavin-3-gallate, etc. and extracts have also been studied and showed extensive health benefits including anticancer, cholesterol-lowing, anti-inflammatory, anti-aging, and against atherosclerosis and coronary heart disease, high blood cholesterol concentrations, and high blood pressure (Mukhtar H. 2000). Anthocyanins are a category of phytochemicals in fruits and vegetables that give them vivid red to blue. Based upon many cell-line studies, animal models, and human clinical trials, Anthocyanins have been suggested possess anti-inflammatory and anti-carcinogenic activity, cardiovascular disease prevention, obesity control, diabetes alleviation, and eye health promoting properties (He J 2010, Kalt W 2010). Human studies with diet rich in anthocyanins suggest it may also protect against development of Parkinson's disease and improve blood pressure (Cassidy J. 2011, Gao X. 2012).
Prior arts have been mostly focused on purify shingle crocin component, either crocin-1 (alpha-crocin) or crocetin. CN102516325 A revealed a method of producing crocin with higher than 95% purity from gardenia. The prior art specifically produces one single crocin component, crocin I (called crocin in prior art) to purity at least 95%. WO2004078695 A1 revealed a method for purification of crocetin. Method in this prior art includes steps of hydrolysis of crocin and then purification of crocetin. Prior arts also include methods of extracting, changing profile of crocin and crocetin or improving recovery of saffron colorant recovery. WO2010094745 A1 and US2010/0210572A1 revealed a method of producing hydrolysate of crocin, resulting in crocin related products with significant amount of crocetin mono esters. WO2004056201A1 revealed a method of increased colorant (crocin and crocetin) recovery from saffron raw material to 95%, while crocin and crocetin together having a pigment concentration of 15-24%. Crocetin and its salts have been chemically synthesized (WO2006104610 A2, U.S. Pat. No.7,351,844 B2). But these chemically synthesized crocetin and its salts are not natural and may not have the same biological and pharmacological properties. US20130156746 A1 revealed a dietary supplement composition which comprises saffron powder and resveratrol. Because saffron has many different grades and varies in its crocin content, it is very difficult to use such a composition for products require quality and efficacy consistency. US20110236481 A1 revealed a composition contains safranal and/or crocin and/or picrocrocin from saffron plant or saffron as satiety agent for treatment of obesity. The active contents of safranal and/or crocin and/or picrocrocin are used at low or diluted level by weight compare to saffron in products and showed to be effective in suppressing hungry (Gout B. 2010).
Applications of enriched and purified natural crocin and/or crocetin enable quality consistency and quantitative amount of crocin and/or crocetin in products. Its use alone or use in combination with other health beneficial phytochemicals in nutraceutical or therapeutic composition is useful in preventing and treating many cancers and disease as well as enhancing health. Combinations of crocin and/or crocetin with other phytochemicals also offer synergistic and broader benefits in preventing and treating cancers and diseases. The invention is focused on crocin and/or crocetin that are extracted, enriched or purified from natural source, gardenia fruits, gardenia extracts or gardenia yellow, to formation unique nutraceutical or pharmaceutical compositions with or without other health promoting phytochemicals, and their uses for (a) prevention or treatment of diseases and conditions including cancers, neurodegenerative diseases, heart diseases, liver diseases, kidney diseases, eye diseases, metabolic syndrome, atherosclerosis, arthritis, inflammations, obesity, or diabetes, etc.; (b) protection of liver, heart, kidney, and other normal organs from injuries or damages; (c) improvement or enhancement of learning/memory ability, immune system, skin health, anti-aging, and over all health.